Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma.
Authors: Jason Westin, Olalekan O. Oluwole, Marie José Kersten, David Bernard Miklos, Miguel-Angel Perales, Armin Ghobadi, Aaron Rapoport, Anna Sureda, Caron Alyce Jacobson, Umar Farooq, Tom van Meerten, Matthew L. Ulrickson, Mahmoud Elsawy, Lori A. Leslie, Sridhar Chaganti, Michael Dickinson, Yin Yang, Marco Andreas Schupp, Christina Ann To, Frederick L. Locke
Journal: Journal of Clinical Oncology (2023)

LBA107 Background: In ZUMA-7 (NCT03391466), axicabtagene ciloleucel (axi-cel) was superior to standard of care (SOC; hazard ratio [HR], 0.398; P&lt;.0001) in the primary analysis of event-free survival as second-line therapy in patients with early relapsed or refractory large B-cell lymphoma (R/R LBCL; Locke et al. NEJM. 2022). In a preplanned interim analysis, median overall survival (OS) was not reached in the axi-cel arm and was 25.7 mo in the SOC arm (HR, 0.71; 95% CI, 0.52-0.97; Locke et al. TCT 2022. Abstract 1). We now report the primary OS analysis of ZUMA-7. Methods: Study procedures and eligibility were previously reported. The intention-to-treat (ITT) primary OS analysis occurred 5 years after the first patient was randomized (01/25/2018) per protocol. A log-rank test stratified by randomization stratification factors compared OS between the 2 arms. In addition to the ITT analysis and to account for subsequent treatment with cellular immunotherapy off protocol in the SOC arm, prespecified sensitivity analyses of OS were conducted using the Rank-Preserving Structural Failure Time (RPSFT) and Inverse Probability of Censoring Weights (IPCW) models. Other endpoints included progression-free survival (PFS) per investigator assessment, OS in key subgroups, and safety. Results: In total, 359 patients were randomly assigned, 180 to axi-cel and 179 to SOC. As of 01/25/2023, at a median follow-up of 47.2 mo, axi-cel demonstrated a statistically significant improvement in OS over SOC (HR [95% CI], 0.726 [0.540-0.977]; stratified log-rank 1-sided P=0.0168 [efficacy boundary, 0.0249]). Median OS was longer with axi-cel vs SOC (not reached vs 31.1 mo, respectively); 48-mo OS estimates were higher with axi-cel (54.6% vs 46.0%, respectively). OS benefit with axi-cel vs SOC was consistent in prespecified key subgroups, including age ≥65 years, primary refractory, early relapse, high-grade B-cell lymphoma, and high second-line age-adjusted IPI. In the SOC arm, 102 (57%) patients received subsequent cellular immunotherapy off protocol. Prespecified OS sensitivity analyses, conducted to address the confounding effects of treatment-switching in the SOC arm, showed an even greater OS benefit with axi-cel vs SOC, with stratified HR (95% CI) of 0.608 (0.449-0.824) by RPSFT and 0.633 (0.409-0.981) by IPCW. PFS by investigator confirmed benefit of axi-cel over SOC (HR [95% CI], 0.506 [0.383-0.669]), with 48-mo PFS estimates of 41.8% vs 24.4%, respectively. No new cytokine release syndrome or neurologic events and no new treatment-related deaths occurred since the primary EFS analysis. The safety profile of axi-cel remained consistent with prior studies. Conclusions: Axi-cel as second-line therapy demonstrated a significant improvement in overall survival over historical standard of care in patients with early relapsed/refractory LBCL. Clinical trial information: NCT03391466 .